Hepatocellular carcinoma (HCC) is a major cause of cancer morbidity and mortality in many parts of Asia, including China and Thailand, and in sub-Saharan Africa, where there are upwards of 600,000 new cases and deaths each year. The impact of HCC is exacerbated by a median age of diagnosis of between 45 and 50 years and it is nearly always fatal. The major known etiological factors associated with development of HCC in these regions are infection with hepatitis B (HBV) and/or hepatitis C (HCV) virus and lifetime exposure to high levels of aflatoxin B1 (AFB1) in the diet. HCC is also the most rapidly rising solid tumor in the US and is overrepresented in minority communities. While knowledge of the etiology of HCC has spurred many mechanistic studies to understand the pathogenesis of this disease, this information is only just beginning to be translated into development of preventive and clinical interventions in high risk populations. The goals of this project are to develop and validate biomarkers reflecting the biological effects of exposures to chemical and viral toxicants in the etiology of liver cancer. In all chronic human diseases, including cancer, ambient exposures to multiple environmental agents are significant contributors. The specific aims of this project are: 1) To develop quantitative mass spectrometric methodologies for analysis of all the major excreted aflatoxin metabolites;2) To determine the power of HBV mutation serum prevalence and aflatoxin-specific p53 mutation serum concentration in predicting cancer outcome and disease risk in cohorts in rural China and West Africa;and 3) To continue to extend our observations on the multipartite roles that aflatoxin, HBV and HCV, an emerging infection, play in the development of HCC in a cohort in Northern Thailand. It is our hypothesis that combined use of biologically effective dose biomarkers, susceptibility biomarkers and genetic biomarkers will reveal the sub-set of high-risk people within the population who would benefit from targeted intervention.